Prevention and treatment of osteoarthritis

Abstract

Subjects lacking Nfat1 display osteoarthritis in weight-bearing joints. Osteoarthritic changes associated with Nfat1 deficiency are characterized by articular cartilage degradation, articular chondrocyte proliferation/clustering, progressive articular surface destruction, periarticular chondro-osteophyte formation, and exposure of thickened subchondral bone. Methods of treating osteoarthritis, methods of diagnosis and early prediction of the onset of osteoarthritis, and methods for screening drug candidates that may be useful for treatment of osteoarthritis are presented.

What is claimed is: 
     
       1. A method of diagnosing primary osteoarthritis and/or predicting susceptibility to primary osteoarthritis in a subject, comprising:
 measuring the subject's Nfat1 protein or gene expression level or an Nfat1 transcription factor activity in a tissue sample selected from cartilage or peripheral blood cells; 
 diagnosing primary osteoarthritis and/or predicting susceptibility to primary osteoarthritis in the subject based on the measuring, wherein the diagnosing includes comparing the subject's Nfat1 protein or gene expression level or the Nfat1 transcription factor activity to a wild-type control Nfat1 protein or gene expression level or an Nfat1 transcription factor activity, wherein having Nfat1 protein or gene expression levels or Nfat1 transcription factor activity reduced by at least 50% relative to the wild-type control is predictive of susceptibility to osteoarthritis; 
 administering at least one bioactive substance selected from the group consisting of an Nfat1 protein and a nucleic acid encoding an Nfat1 protein to the subject; and 
 determining whether the bioactive substance increases at least one of Nfat1 protein expression, Nfat1 gene expression, or Nfat1 transcription factor activity in cartilage or peripheral blood cells in the subject. 
 
     
     
       2. A method as recited in  claim 1 , wherein the tissue sample includes articular cartilage cells. 
     
     
       3. A method as recited in  claim 1 , further comprising measuring type II collagen production by articular cartilage cells in the subject. 
     
     
       4. A method as recited in  claim 1 , further comprising measuring aggrecan production by articular cartilage cells in the subject. 
     
     
       5. A method as recited in  claim 1 , further comprising probing the subject's genome for sequence variations in Nfat1. 
     
     
       6. A method as recited in  claim 1 , further comprising determining whether the subject has degenerative articular cartilage disease. 
     
     
       7. A method as recited in  claim 1 , further comprising measuring articular cartilage degeneration. 
     
     
       8. A method as recited in  claim 1 , measuring at least one of an activity or a concentration of at least one downstream effector of Nfat1. 
     
     
       9. A method as recited in  claim 8 , wherein Nfat1 and/or the downstream effectors of Nfat1 affect levels of at least one of:
 matrix metalloproteinase 1a (Mmp1a); 
 matrix metalloproteinase 13 (Mmp13); 
 Adamts5 (i.e., a disintegrin and metalloproteinase with thrombospondin motifs); 
 tissue inhibitor of metalloproteinase-1 (Timp1); 
 aggrecan; 
 a collagen protein; 
 β-catenin; 
 interleukin-1β (IL-1β); 
 interleukin-6 (IL-6); or 
 interleukin-17α (IL-17α). 
 
     
     
       10. A method of diagnosing primary osteoarthritis and/or predicting susceptibility to primary osteoarthritis in a subject, comprising:
 measuring a subject's Nfat1 protein or gene expression level or an Nfat1 transcription factor activity in a tissue sample selected from cartilage or peripheral blood cells; and 
 diagnosing primary osteoarthritis and/or predicting susceptibility to primary osteoarthritis in the subject based on the measuring, wherein having Nfat1 protein or gene expression levels or Nfat1 transcription factor activity reduced by at least 50% relative to the wild-type control is predictive of susceptibility to osteoarthritis; and 
 administering an agent to the subject to increase Nfat1 protein or gene expression or to increase Nfat1 transcription factor activity in cartilage tissue in the subject, wherein the agent is selected from the group consisting of an Nfat1 protein, a nucleic acid encoding an Nfat1 protein, and combinations thereof. 
 
     
     
       11. A method as recited in  claim 10 , further comprising determining whether the administered agent increases intracellular synthesis of Nfat1 protein, increases nuclear translocation of Nfat1 protein, increases Nfat1 transcription factor activity, and/or affects a downstream effector of Nfat1. 
     
     
       12. A method of  claim 11 , further comprising subsequent to administering the agent: measuring the subject's Nfat1 protein or gene expression level or an Nfat1 transcription factor activity in cartilage or peripheral blood cells; and comparing the subject's Nfat1 protein or gene expression level or the Nfat1 transcription factor activity to a wild-type control Nfat1 protein or gene expression level or an Nfat1 transcription factor activity.